Any reference to background art herein is not to be construed as an admission that such art constitutes common general knowledge in Australia or elsewhere.
Adult mesenchymal stem cells (MSCs) are an abundant source of self-renewing, multipotent undifferentiated cells that can be readily isolated from bone marrow, adipose tissue, muscle and synovium, and expanded in ex vivo culture. The ability of these cells to differentiate into bone, cartilage, adipose, tendon and other cells of the mesenchymal lineage under appropriate stimuli offers the potential for the regeneration and repair of the musculoskeletal system by their direct application to sites of injury [1-3] or by their incorporation into bioscaffolds and transplantation into the sites of the tissue defect [1,4,5].
Stromal tissue in the bone marrow consists of a heterogeneous population of MSCs that occupy a perivascular niche. Studies have provided evidence for the existence within this niche of smaller precursor stem cell populations that exhibit extensive proliferative and multilineage differentiative capacity and can be distinguished by their expression of certain cell surface antigens [6,7]. These undifferentiated mesenchymal precursor cells (MFCs) can be isolated from bone marrow aspirates using techniques such as magnetic activated cell sorting in combination with antibodies that identify STRO-1, VCAM-1 (CD106), STRO-3 (tissue nonspecific alkaline phosphatase), STRO-4 (HSP-90b) and CD146 [6,7].
Using this approach, a homogeneous population of quiescent MPCs can be obtained that lack the phenotypic characteristics of leukocytes and mature stromal elements and exhibit extensive proliferative capacity while retaining the ability to differentiate into bone, cartilage and adipose tissues.
WO 2009/018613 in the name of Angioblast Systems Inc disclosed the use of MPCs in treating diseases with an underlying etiology of inflamed or degraded connective tissue such as, for example, degenerative cervical and lumbar disc conditions. The intra-articular administration of MPCs was described as providing a chondroprotective effect in joints with pre-existing osteoarthritis and was found to lead to the growth of cartilage tissue in synovial joints and the nucleus pulposus of intervertebral discs.
Ghosh et al [8] demonstrated that the presence of the semi-synthetic sulphated polysaccharide, pentosan polysulfate (PPS), induced the in vitro proliferation and chondrogenic differentiation of MPCs even absent the addition of growth factors or other chondroinductive supplements. It was postulated that a treatment regime combining PPS with MPCs could benefit patients requiring repair and reconstitution of injured and degenerate cartilaginous tissues. The specificity of PPS as a promoter of chondrogenesis and the unpredictability of the success of other polysaccharides was demonstrated by the fact that dextran sulphate and heparin did not show any success in this role while hyaluronan showed some stimulation of MPCs to synthesis proteoglycan (PG) when present at low concentrations but at higher concentrations actually inhibited PG synthesis.
The use of MPCs, with or without a promoter such as PPS, opens up a wide range of potential treatment methodologies to address diseases or conditions resulting from degradation of cartilaginous tissues. Intervertebral disc (IVD) degeneration is just such a condition which can cause great discomfort and reduce quality of life significantly for a sufferer. Current treatments include immobilization and surgical intervention. Neither approach actually repairs the underlying tissue degeneration and recurrence of symptoms is likely.
MPCs thus present the possibility of a new treatment paradigm. However, their use will require both effective delivery and careful control of the chemical and physical cues provided to ensure appropriate differentiation to provide regenerated or repaired tissue.